Window of Opportunity Study of Pembrolizumab Alone and in Combinations in Bladder Cancer

NCT03978624 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 1 other identifier: LCCC1827
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

This is an open-label, window of opportunity platform study for subjects with muscle-invasive bladder cancer (MIBC) who are deemed ineligible or refuse cisplatin-based neoadjuvant chemotherapy and are scheduled to undergo definitive surgery (radical cystectomy), or are planning to undergo trimodality therapy (maximal transurethral resection of the bladder tumor followed by concurrent chemoradiation). The primary objective of this study is to assess changes to immunogenomic markers after treatment with pembrolizumab alone and in combination with the selective class I histone deacetylase (HDAC) inhibitor (entinostat).

Conditions

Bladder Cancer

Keywords

Muscle Invasive Bladder Cancer; MIBC; pembrolizumab; entinostat

Outcome Measures

Primary Outcomes (1)

• Changes in CD8 T Cell Immune Gene Signature in the Pembrolizumab + Entinostat Group and the Pembrolizumab Group

  Gene expression levels with the CD8 T cell gene signature were measured using RNA sequencing. The expression level of each gene in the signature were log2 transformed and the mean of the signature genes was calculated in each sample. Then the mean expression of signature in each sample was compared to the average expression and variability across other sample to center the expression values (mean = 0) and scale them by standard deviation and generate a Z-score. Change in z-score was then calculated between pre- and post-treatments for each individual patient and then changes in z-score were compared between treatment arms. An increase in Z-score with treatment denotes an increase in expression of the immune gene signature (IGS).

  Pre-treatment and at time of definitive treatment within 10 weeks after starting neoadjuvant treatment

Secondary Outcomes (6)

• Change From Baseline in Number and Character of Neoantigens

  Less than 10 weeks

• Change From Baseline in Signal Transducer and Activator of Transcription Factors (STAT) and Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells (NF-κB) Gene Signatures and Histone Acetylation (H3K9Ac, H3K27Ac, and Others) Levels

  10 weeks

• Frequency and Severity of Attributed Adverse Events as Assessed by CTCAE v5.0

  10 weeks

• Proportion of Patients Who Have no Cancer in Tissue Samples at Surgery (Pathologic Complete Response, or Only Non-invasive Cancer (Pathologic Partial Response)

  10 weeks

• Event Free Survival (EFS)

  Up to 3 years

Study Arms (2)

A: Pembrolizumab alone

EXPERIMENTAL

Subjects will be administered pembrolizumab alone 200 mg IV on day 1 and day 22

Drug: Pembrolizumab; Procedure: Procedure/Surgery

B: Pembrolizumab plus Entinostat

EXPERIMENTAL

Subjects will be administered pembrolizumab on day 1 and day 22 and entinostat 5 mg given orally on day 1, day 8 and day 15

Drug: Pembrolizumab; Drug: Entinostat; Procedure: Procedure/Surgery

Interventions

Pembrolizumab DRUG

200 mg IV on day 1 and day 22

Also known as: Keytruda

A: Pembrolizumab alone; B: Pembrolizumab plus Entinostat

Entinostat DRUG

5 mg given orally on day 1, day 8 and day 15

Also known as: SNDX-275, MS-275

B: Pembrolizumab plus Entinostat

Procedure/Surgery PROCEDURE

A radical cystectomy is a surgical procedure to remove the entire urinary bladder and maximal transurethral resection of bladder tumor (TURBT) is a surgical procedure used to remove as much of the bladder tumor as possible.

Also known as: Radical cystectomy or maximal TURBT

A: Pembrolizumab alone; B: Pembrolizumab plus Entinostat

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information.
• Subjects must agree to donate tumor tissue from their transurethral resection of the bladder tumor (TURBT) and from their cystectomy, as well as agree to donate whole blood prior to initiating therapy, and at cystectomy.
• Age ≥18 years at the time of consent.
• Eastern Cooperative Oncology Group performance status of ≤ 2.
• Histological confirmation of urothelial carcinoma of the bladder; those with mixed histology, including a component of urothelial carcinoma, are eligible. Pure small cell carcinoma, pure adenocarcinoma, and pure squamous cell carcinoma are excluded.
• Subject has clinical stage T2-T4a N0/X M0 urothelial carcinoma. Clinical T stage is based on the pre-study standard of care transurethral resection of the bladder tumor (TURBT) sample and imaging studies (abdominal/pelvic CT or MRI scan and CT scan of the chest performed within 4 weeks prior to treatment initiation).
• Available formalin-fixed paraffin-embedded (FFPE) archival tumor specimen that contains sufficient tissue to generate at least 15 (preferably 20) unstained slides, each with tissue sections that are 5 - 10 microns thick.
• Subject is planned to undergo definitive surgery (radical cystectomy).
• Subject demonstrates adequate organ function as defined by the protocol; all screening laboratory assessments should be performed within 10 days of treatment initiation.
• Subject refuses to receive or is ineligible to receive cisplatin-based neoadjuvant chemotherapy. Determination of ineligibility for cisplatin is based on at least one of the following criteria:
• Eastern Cooperative Oncology Group performance status of 2
• Glomerular filtration rate (GFR) per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation ≤ 60 mL/min
• NCI CTCAE v5.0 Grade ≥ 2 hearing loss
• NCI CTCAE v5.0 Grade ≥ 2 neuropathy
• Female subjects of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of the study treatment.

You may not qualify if:

• Subject is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of pembrolizumab.
• Subject has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Inhaled and topical steroids are allowed.
• Subject has a known history of active tuberculosis.
• Subject has known hypersensitivity to pembrolizumab or any of its excipients.
• For subjects in arm 2 only, to benzamide or inactive ingredients of entinostat.
• Subject has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
• Subject has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Subject has a history of (non-infectious) pneumonitis that required steroids or a current pneumonitis.
• Subject has an active infection requiring systemic therapy.
• Subject has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Please note that subjects with Grade ≥2 peripheral neuropathy, are allowed on this study.
• Subject has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Subject is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Subject has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Subject has had prior systemic cytotoxic chemotherapy for urothelial carcinoma (prior intravesicular chemotherapies are permitted).
• Subject is receiving histone deacetylase inhibitors, including valproic acid, DNA methyltransferase inhibitors.

Sponsors & Collaborators

• UNC Lineberger Comprehensive Cancer Center: lead
• Merck Sharp & Dohme LLC: collaborator
• Syndax Pharmaceuticals: collaborator

Study Sites (2)

Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Related Links

• University of North Carolina Lineberger Comprehensive Cancer Center Clinical Trials

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

pembrolizumab; entinostat; Surgical Procedures, Operative; Cystectomy

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Urologic Surgical Procedures; Urogenital Surgical Procedures

Results Point of Contact

• Title: Melahat Canter
• Organization: UNC Lineberger Comprehensive Cancer Center

Melahat_Canter@med.unc.edu

919-962-0000

Study Officials

• Tracy L Rose, MD

  UNC- Chapel HIll

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 22, 2019
• First Posted: June 7, 2019
• Study Start: September 23, 2020
• Primary Completion: March 25, 2024
• Study Completion (Estimated): November 22, 2026
• Last Updated: October 15, 2025
• Results First Posted: October 7, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)